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Abstracts Diabetic cardiomyopathy (DCM) is diagnosed when patients with diabetes develop ventricular dysfunction but do not exhibit coronary atherosclerosis or hypertension. Cortex Mori (CM) Radicis,he epidermis of the root of Morus alba L, has been traditionally used for cough treatment in oriental medicine. In this study, we investigated the protection of myocardium by CM in streptozotocin (STZ)-induced diabetic rats and the underlying mechanisms. Diabetes was induced in rats by an injection of STZ at 25 mg/kg. The animals were randomly divided into 4 groups: control, diabetes, diabetes with CM treatment, diabetes with CM preventative treatment. Pathological changes were examined by hematoxylin-eosin staining. Extracellular matrix content was assessed by Masson’s trichrome staining and Western blot. Endoplasmic reticulum (ER) stress-associated molecules and main components of the mitogen-activated protein kinase (MAPK) pathway were also measured by Western blot. Myocardial damages were induced by the injection of STZ as evidenced by abnormal blood glucose and pathological cardiac changes. Administration of CM markedly ameliorated myocardial damages such as cardiac hypertrophy and fibrosis. ER stress was down-regulated, and p38 and ERK were suppressed by CM. Thus, CM may have therapeutic potential in the treatment of DCM by attenuating ER stress and ERK and p38 MAPK activation. [ABSTRACT FROM AUTHOR]

miRNAs Regulate hERG Background The human ether-a-go-go-related gene (hERG) is the major molecular component of the rapidly activating delayed rectifier K+ current (Ikr). Impairment of hERG function is believed to be a mechanism causing long-QT syndromes (LQTS). Growing evidences have shown that microRNAs (miRNAs) are involved in functional modulation of the hERG pathway. The purpose of this study was to screen and validate miRNAs that regulate the hERG pathway. The miRNAs identified in this study will provide new tools to assess the mechanism of LQTS. Methods Six miRNAs were selected by algorithm predictions based on potential interaction with hERG. The effects of each miRNA on hERG were assessed by use of the Dual-Luciferase Reporter assay system, qRT-PCR, Western blotting, and confocal fluorescence microscopy. Furthermore, whole-cell patch clamp technique was used to validate the effect of miR-103a-1 on the electrophysiological characteristic of the Ikr of the hERG protein channel. Results miR-134, miR-103a-1, miR-143, and miR-3619 significantly downregulated luciferase activity (P < 0.05) in a reporter test system. These 4 miRNAs significantly suppressed expression of hERG mRNA and protein in U2OS cells (P < 0.05).Corresponding AMOs rescued expression of hERG mRNA and protein. Confocal microscopy showed that all 4 miRNAs reduced the expression of both immature and mature hERG protein. miR-103a-1 decreased the maximum current and tail current amplitudes of hERG channel. Conclusions Expression and functions of hERG are regulated by specific miRNAs. [ABSTRACT FROM AUTHOR]

This study compared microRNA (miRNA) expression profiles between rheumatic heart disease (RHD) patients and healthy controls to investigate their differential expression and help elucidate their mechanisms of action. Microarray analysis was used to measure miRNA expression, and a total of 133 miRNAs were shown to be significantly upregulated in RHD patients compared with controls, including miR-1183 and miR-1299. A total of 137 miRNAs, including miR-4423-3p and miR-218-1-3p, were significantly downregulated in RHD patients. Quantitative real-time-PCR confirmed microarray findings for miR-1183 and miR-1299 in both tissue and plasma. Bioinformatic predictions were also made of differentially expressed miRNAs as biomarkers in RHD by databases and GO/pathway analysis. Furthermore, we investigated miR-1183 and miR-1299 expression in RHD patients with secondary pulmonary hypertension (PAH). Our findings identified an important role for miR-1299 as a direct regulator of RHD, while the observed difference in expression of miR-1183 between RHD-PAH patients with high or low pulmonary artery pressure suggests that miR-1183 overexpression may reflect pulmonary artery remodeling. miR-1183 and miR-1299 appear to play distinct roles in RHD pathogenesis accompanied by secondary PAH and could be used as potential biological markers for disease development. [ABSTRACT FROM AUTHOR]

Abstract: Aim: HFE gene variants can cause hereditary hemochromatosis (HH) that often comes along with an increased risk of coronary heart disease (CHD). The goal of our study is to assess the contribution of four HFE gene variants to the risk of CHD. Methods and results: We conducted four meta-analyses of the studies examining the association between four HFE gene variants and the risk of CHD. A systematic search was conducted using MEDLINE, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI), Wanfang Chinese Periodical. Results: Meta-analyses showed that HFE rs1799945-G allele was associated with a 6% increased risk of CHD (P =0.02, odds ratio (OR)=1.06, 95% confidence interval (CI)=1.01–1.11). However, no association between the other three HFE gene variants (rs1800562, rs1800730, and rs9366637) and CHD risk was observed by the meta-analyses (all P values>0.05). In addition, the results of our case–control study indicated that rs1800562 and rs1800730 were monomorphic, and that rs1799945 and rs9366637 were not associated with CHD in Han Chinese. Conclusions: Our meta-analysis suggested that a significant association existed between rs1799945 mutation and CHD, although this mutation was rare in Han Chinese. [Copyright &y& Elsevier]

Background: The role of diet choline in atherosclerotic cardiovascular disease (ASCVD) is uncertain. Findings from animal experiments are contradictory while there is a lack of clinical investigations. This study aimed to investigate the association between choline intake and ASCVD based on individuals from the National Health and Nutrition Examination Survey (NHANES) database. Methods: This cross-sectional study was conducted in 5525 individuals from the NHANES between 2011 and 2018. Participants were categorized into the ASCVD (n = 5015) and non-ASCVD (n = 510) groups. Univariable and multivariable-adjusted regression analyses were employed to investigate the relationship between diet choline and pertinent covariates. Logistic regression analysis and restricted cubic spline analysis were used to evaluate the association between choline intake and ASCVD. Results: ASCVD participants had higher choline intake compared to those without ASCVD. In the higher tertiles of choline intake, there was a greater proportion of males, married individuals, highly educated individuals, and those with increased physical activity, but a lower proportion of smokers and drinkers. In the higher tertiles of choline intake, a lower proportion of individuals had a history of congestive heart failure and stroke. After adjusting for age, gender, race, ethnicity, and physical activity, an inverse association between choline intake and heart disease, stroke, and ASCVD was found. A restricted cubic spline analysis showed a mirrored J-shaped relationship between choline and ASCVD, stroke and congestive heart failure in males. There was no association between dietary choline and metabolic syndrome. Conclusion: An inverse association was observed between choline intake and ASVCD among U.S. adults. Further large longitudinal studies are needed to test the causal relationship of choline and ASVCD. [ABSTRACT FROM AUTHOR]

The aggregation of medin forming aortic medial amyloid is linked to arterial wall degeneration and cerebrovascular dysfunction. Elevated levels of arteriolar medin are correlated with an increased presence of vascular amyloid- β (A β) aggregates, a hallmark of Alzheimer's disease (AD) and vascular dementia. The cross-interaction between medin and A β results in the formation of heterologous fibrils through co-aggregation and cross-seeding processes both in vitro and in vivo. However, a comprehensive molecular understanding of the cross-interaction between medin and A β —two intrinsically disordered proteins—is critically lacking. Here, we employed atomistic discrete molecular dynamics simulations to systematically investigate the self-association, co-aggregation and also the phenomenon of cross-seeding between these two proteins. Our results demonstrated that both A β and medin were aggregation prone and their mixture tended to form β -sheet-rich hetero-aggregates. The formation of A β -medin hetero-aggregates did not hinder A β and medin from recruiting additional A β and medin peptides to grow into larger β -sheet-rich aggregates. The β -barrel oligomer intermediates observed in the self-aggregations of A β and medin were also present during their co-aggregation. In cross-seeding simulations, preformed A β fibrils could recruit isolated medin monomers to form elongated β -sheets. Overall, our comprehensive simulations suggested that the cross-interaction between A β and medin may contribute to their pathological aggregation, given the inherent amyloidogenic tendencies of both medin and A β. Targeting medin, therefore, could offer a novel therapeutic approach to preserving brain function during aging and AD by improving vascular health. [ABSTRACT FROM AUTHOR]

Background: Observational studies have suggested that immune-mediated inflammatory diseases (IMIDs) are associated with a higher risk of valvular heart disease (VHD). But the potential causal association is not clear. Therefore, we used Mendelian randomization (MR) analysis to assess the causal association of IMIDs with VHD risk. Methods: A two-sample MR analysis was performed to confirm the causal association of several common IMIDs (systemic lupus erythematosus, SLE; rheumatoid arthritis, RA; multiple sclerosis, MS; ankylosing spondylitis, AS; psoriasis, PSO; inflammatory bowel disease, IBD) with the risk of VHD. The exposure data is derived from published genome-wide association studies (GWASs) and outcome data come from the FinnGen database (47,003 cases and 182,971 controls). Inverse-variance weighted (IVW), MR-Egger, and weighted median methods were performed to assess the causal association. The study design applied univariable MR and multivariable MR. Results: The MR analysis indicated that several genetically predicted IMIDs increased the risk of VHD, including SLE (odds ratio (OR) = 1.014; 95% confidence interval (CI) = < 1.001,1.028 > ; p = 0.036), RA (OR = 1.017; 95% CI = < 1.002,1.031 > ; p = 0.025), and IBD (OR = 1.018; 95% CI = < 1.002,1.033 > ; p = 0.023). Multivariable MR indicated that the adverse effect of these IMIDs on VHD was dampened to varying degrees after adjusting for smoking, obesity, coronary artery disease, and hypertension. Conclusion: Our findings support the first genetic evidence of the causality of genetically predicted IMIDs with the risk of developing into VHD. Our results deliver a viewpoint that further active intervention needs to be explored to mitigate VHD risk in patients with SLE, RA, and IBD. Key Points • Genetically predicted systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD) are causally associated with valvular heart disease (VHD). • To reduce the risk of VHD in patients with SLE, RA, and IBD, active interventions should be further explored. [ABSTRACT FROM AUTHOR]

Atherosclerosis, the pathophysiological basis of most malignant cardiovascular diseases, remains a global concern. Transcription factors play a key role in regulating cell function and disease progression in developmental signaling pathways involved in atherosclerosis. Activated transcription factor (ATF) 3 is an adaptive response gene in the ATF/cAMP response element binding (CREB) protein family that acts as a transcription suppressor or activator by forming homodimers or heterodimers with other ATF/CREB members. Appropriate ATF3 expression is vital for normal physiological cell function. Notably, ATF3 exhibits distinct roles in vascular endothelial cells, macrophages, and the liver, which will also be described in detail. This review provides a new perspective for atherosclerosis therapy by summarizing the mechanism of ATF3 in atherosclerosis, as well as the structure and pathophysiological properties of ATF3. Key messages: • In endothelial cells, ATF3 overexpression aggravates oxidative stress and inflammation. • In macrophages and liver cells, ATF3 can act as a negative regulator of inflammation and promote cholesterol metabolism. • ATF3 can be used as a potential therapeutic factor in the treatment of atherosclerosis. [ABSTRACT FROM AUTHOR]

• Overview of hydrogel biosensors in the field of medical electronics. • The summary of the characteristics of non-implantable and implantable hydrogel biosensors. • Review of the design methodologies and application scenarios for integrated multifunctional hydrogel biosensors. • Prospects for the future development of more biocompatible hydrogel bioelectronics. Hydrogels and their sensors are emerging as key players in biomedical electronics, offering flexible, programmable structures and functions. Hydrogel-based sensors with stress–strain and electrophysiological sensing capabilities have consistently attracted interest. However, non-implantable hydrogel sensors often face challenges such as low sensitivity and slow response times, hindering their ability to detect subtle movements and causing delays in signal transmission. On the other hand, implantable hydrogel sensors, known for their biocompatibility and ionic conductivity, are better suited for long-term in vivo monitoring. Yet, their interface with biological tissues can lead to high impedance, adversely affecting signal quality and reducing sensor effectiveness. Furthermore, certain implantable hydrogel sensors may have limitations in light transmission properties, posing challenges in co-transmitting photoelectric signals for various applications. To address these challenges, researchers have been focusing on optimizing the mechanical and electrical properties of hydrogels. This involves modifications in precursor materials and structural designs, leading to the integration of multiple functionalities and significant performance improvements in hydrogel sensors. This systematic review covers existing studies on hydrogel sensors for biomedical electronics, from basic functionalities to more complex ones, and includes both non-implantable and implantable devices. Additionally, it provides insights into the future design principles and potential application scenarios for the next generation of multifunctional hydrogel sensors. [ABSTRACT FROM AUTHOR]

Aims: To investigate the association of ABCG1, GALNT2 and HMGCR genes promoter DNA methylation with coronary heart disease (CHD) and explore the interaction between their methylation status and the CHD patients' clinical characteristics in Han Chinese population. Methods and results: Methylation-specific polymerase chain reaction (MSP) technology was used to examine the role of the aberrant gene promoter methylation in CHD in Han Chinese population. A total of 85 CHD patients and 54 participants without CHD confirmed by angiography were recruited. 82.8% of the participants with ABCG1 gene promoter hypermethylation have CHD, while only 17.4% of the participants without hypermethylation have it. The average age of the participants with GALNT2 gene promoter hypermethylation is 62.10±8.21, while that of the participants without hypermethylation is 57.28±9.87; in the former group, 75.4% of the participants have CHD, compared to only 50% in the latter group. As for the HMGCR gene, the average age of the participants with promoter hypermethylation is 63.24±8.10 and that of the participants without hypermethylation is 57.79±9.55; its promoter hypermethylation is likely to be related to smoking. Our results indicated a significant statistical association of promoter methylation of the ABCG1 gene with increased risk of CHD (OR = 19.966; 95% CI, 7.319–54.468; P*<0.001; P*: adjusted for age, gender, smoking, lipid level, hypertension, and diabetes). Similar results were obtained for that of the GALNT2 gene (OR = 2.978; 95% CI, 1.335–6.646; P* = 0.008), but not of HMGCR gene (OR = 1.388; 95% CI, 0.572–3.371; P* = 0.469). Conclusions: The present work provides evidence to support the association of promoter DNA methylation status with the risk profile of CHD. Our data indicates that promoter DNA hypermethylation of the ABCG1 and GALNT2 genes, but not the HMGCR gene, is associated with an increased risk of CHD. CHD, smoking and aging are likely to be the important factors influencing DNA hypermethylation. [ABSTRACT FROM AUTHOR]

Background: Treatment of LQT2 is inadequate. Many drugs which can pharmacologically rescue defective protein trafficking in LQT2 also result in potent blockade of HERG current, negating their therapeutic benefit. It is reported that PD-118057 and thapsigargin can rescue LQT2 without hERG channel blockade, but the precise mechanism of action is unknown. Furthermore, the effect of PD-118057 and thapsigargin on the dominant negative E637K-hERG mutant has not been previously investigated. Objective: In this study, we investigated: (a) the effect of PD-118057 and thapsigargin on the current amplitudes of WT-hERG and WT/E637K-hERG channels; (b) the effect of PD-118057 and thapsigargin on the biophysical properties of WT-hERG and WT/E637K-hERG channels; (c) whether drug treatment can rescue channel processing and trafficking defects of the WT/E637K-hERG mutant. Methods: The whole-cell Patch-clamp technique was used to assess the effect of PD-118057 and thapsigargin on the electrophysiological characteristics of the rapidly activating delayed rectifier K+ current (Ikr) of the hERG protein channel. Western blot was done to investigate pharmacological rescue on hERG protein channel function. Results: In our study, PD-118057 was shown to significantly enhance both the maximum current amplitude and tail current amplitude, but did not alter the gating and kinetic properties of the WT-hERG channel, with the exception of accelerating steady-state inactivation. Additionally, thapsigargin shows a similar result as PD-118057 for the WT-hERG channel, but with the exception of attenuating steady-state inactivation. However, for the WT/E637K-hERG channel, PD-118057 had no effect on either the current or on the gating and kinetic properties. Furthermore, thapsigargin treatment did not alter the current or the gating and kinetic properties of the WT/E637K-hERG channel, with the exception of opening at more positive voltages. Conclusion: Our findings illustrate that neither PD-118057 nor thapsigargin play a role in correcting the dominant-negative effect of the E637K-hERG mutant. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To explore the association of rs11206510 (PCSK9 gene) and rs1122608 (LDLR gene) polymorphisms with coronary heart disease (CHD) in Han Chinese. Methods: A total of 813 participants (290 CHD cases, 193 non-CHD controls and 330 healthy controls) were recruited in the case-control study. DNA genotyping was performed on the SEQUENOM® Mass–ARRAY iPLEX® platform. χ2-test was used to compare the genotype distribution and allele frequencies. Two meta-analyses were performed to establish the association between the two polymorphisms with CHD. Results: No significant associations between the two SNPs and the risk of CHD were observed in the present study. The meta-analysis of rs11206510 of PCSK9 gene comprises 11 case-control studies with a total of 69,054 participants. Significant heterogeneity was observed in Caucasian population in subgroup analysis of the association studies of rs11206510 with CHD (P =0.003, I 2 =67.2%). The meta-analysis of LDLR gene rs1122608 polymorphism comprises 7 case-control studies with a total of 20,456 participants and the heterogeneity of seven studies was minimal (P =0.148, I 2 =36.7%). Conclusion: The results of the meta-analyses indicated that both SNPs were associated with CHD in Caucasians (P <0.05) but not in Asians. The results from our case-control study and meta-analyses might be explained by genetic heterogeneity in the susceptibility of CHD and ethnic differences between Asians and Caucasians. [Copyright &y& Elsevier]

Abstract: The goal of our study is to evaluate the contribution of CXCL12 rs1746048 (hg19, chr10:44775574) to the risk of CHD in Han Chinese, and to summarize its role in CHD through meta-analysis of existing studies among various ethnic groups. Significant association is observed between rs1746048-C and an increased risk of CHD in Han Chinese (χ2 =5.41, df=1, P=0.02). Post hoc analysis reveals an even stronger association of rs1746048 with the risk of CHD for subjects aged 65years or older (genotype: χ2 =8.39, df=2, P=0.015; allele: χ2=9.13, df=1, P=0.003, odd ratio (OR)=1.91, 95% confidential interval (CI)=1.25–2.91). A break down analysis by gender shows that rs1746048 is likely a CHD risk factor under the recessive model in males (CC+CT versus TT: P=0.05, χ2 =3.59, df=1, OR=1.72, 95% CI=1.00–3.04). In addition, a meta-analysis of ten studies among over 107,000 individuals confirms that rs1746048 is a risk factor of CHD (P<0.0001, OR=1.12, 95% CI=1.09–1.15) and this agrees with the findings of our case–control study in Han Chinese. [Copyright &y& Elsevier]

Abstract: Introduction: Peden et al. have revealed a significant association between four new risk loci and coronary heart disease (CHD) in Europeans and South Asians. The goal of this study is to evaluate the contribution of these genetic loci to CHD risk in Han Chinese. Methods: We recruited 161 CHD patients and 112 controls proved by angiography originated from Ningbo in the Eastern China, and performed a case-control association study of the four significant SNPs. Results: Among the four tested SNPs, we found a significant association of rs974819 in PDGFD gene with CHD (allele p=0.04; OR=1.45, 95% CI=1.02 - 2.08) and the allele A/G of rs974819 shows significant difference in females (allele p=0.04; OR=1.83, 95% CI=1.01 - 3.31). A further meta-analysis showed that rs974819 of PDGFD gene was significantly associated with an increasing risk of CHD (OR=1.08, 95% CI=1.05 - 1.11) in both Europeans and South Asians including Han Chinese. Conclusions: Our findings suggests that rs974819 of PDGFD is also a CHD risk factor in Han Chinese. In addition, it presents a sex-dependent genetic effect. [Copyright &y& Elsevier]